A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD

• ClinicalTrials.gov Identifier: NCT02451696
• Recruitment Status: Completed
• First Posted: May 22, 2015
• Results First Posted: September 1, 2021
• Last Update Posted: September 1, 2021
• Sponsor: NYU Langone Health
• Information provided by (Responsible Party): NYU Langone Health

Tracking Information

• First Submitted Date: October 8, 2014
• First Posted Date: May 22, 2015
• Results First Submitted Date: November 17, 2020
• Results First Posted Date: September 1, 2021
• Last Update Posted Date: September 1, 2021
• Study Start Date: January 2014
• Actual Primary Completion Date: December 8, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 31, 2021)

Number of Patients With Adverse Events [ Time Frame: 6 weeks ]

.Adverse event monitoring should be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment

Original Primary Outcome Measures (submitted: May 21, 2015)

Number of patients with adverse events [ Time Frame: 6 weeks ]

.Adverse event monitoring should be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment

Current Secondary Outcome Measures (submitted: August 31, 2021)

• Blood Everolimus Levels [ Time Frame: 28 days ]
  mTOR signaling in blood
• Blood Total VEGF Levels (Not Only VEGF-D) [ Time Frame: 28 days ]
• mTOR Brain Tissue-S6 Phosphate by Western Blot [ Time Frame: 28 days ]
• HMGB1 Expression in Brain Tissue [ Time Frame: 28 days ]
  HMGB1 expression is measured through label-free quantification (LFQ). LFQ is a method in mass spectroscopy that determines the relative amount of proteins in biological samples. The unit of measure is LFQ intensity; a higher LFQ intensity indicates greater HMGB1 expression.

Original Secondary Outcome Measures (submitted: May 21, 2015)

Number of participants with reduced mTOR signaling [ Time Frame: 28 days ]

MTor signaling is measured by peripheral VEGF-D levels, Blood and brain levels of cytokines (and TNF-α) and inflammatory proteins (HMGB1)at the time of surgery, Brain glutamate and GABA receptor expression at the time of surgery, and Blood levels of everolimus at the time of surgery

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
• Official Title: A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD

Brief Summary

The purpose of this study is to measure if the drug called Everolimus effects mTOR signaling (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be undergoing brain surgery. One group of patients will be treated with Everolimus, and another will not. Researchers will determine if there is a difference in mTOR signaling between the patients who were treated with Everolimus and those who were not. Previous studies have suggested that Everolimus may reduce seizure activity in TSC patients by decreasing mTOR signaling. Since patients with FCD may also have excess mTOR signaling brain activity, Everolimus may also reduce seizure activity in these patients.

The drug Everolimus is approved by the Food and Drug Administration to treat specific types of breast, pancreatic, and kidney cancer, a kidney tumor called an angiomyolipoma (common in patients with TSC), and TSC patients who have a brain tumor called a subependymal giant cell astrocytoma (SEGA). However, in this research it is considered to be an investigational since it is not approved for reduction in mTOR signaling and a decrease in seizure frequency. Researchers believe that Everolimus may be useful in reducing something called cortical hyperexcitability, which is the excess brain activity that can contribute to seizures.

Detailed Description

This is a single center open-label pilot clinical trial of patients with TRE, ages 1 to 40 years old, with TSC or FCD who are scheduled for epilepsy surgery. Patients will be treated with everolimus for 7 to 28 days prior to epilepsy surgery with extension of time from 7 to 28 days in successive cohorts of patients. The initial cohort of at least three patients will be treated for 7 days and after the safety of therapy is assured for this group, there will be an extension of the treatment to 14 days for at least three patients. This will be extended at one week intervals/three patient groups to a maximum treatment duration of 28 days. Resected brain tissue will be analyzed for activation of mTORC1 and mTORC2 signaling pathways, glutamatergic and GABA-ergic neurotransmission using histochemistry, genetic analysis, as well as extracellular field recordings in acute ex-vivo brain slices from surgery. A blood sample, collected at the time of surgery, will be analyzed for everolimus levels and VEGF-D. All patients will undergo standardized intra-operative ECoG recordings over the primary epileptogenic region and reviewed blindly.

Subjects will be in the study for 7-28 days. The investigators will study variables listed in specific aims 1 and 2 in TSC and FCD patients treated with 7 to 28 days of everolimus and compare these to untreated control patients with TRE and TSC or FCD. A concurrent comparison group of 12 subjects will also be enrolled. They will all be undergoing routine surgery for the diagnosis of TRE with TSC or FCD.

All study procedures will be performed at the Comprehensive Epilepsy Center (CEC) with the exception of the surgery, which will be performed at Tisch Hospital.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Epilepsy
• Tuberous Sclerosis Complex
• Focal Cortical Dysplasia

Intervention

Drug: Everolimus

This study will measure if the drug called Everolimus effects mTOR signaling (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be undergoing brain surgery. One group of patients will be treated with Everolimus, for 7-28 days prior to epilepsy surgery and another will not. We will determine if there is a difference in mTOR signaling between the patients who were treated with Everolimus and those who were not

Other Name: Trade Name: Afinitor®

Study Arms

• Experimental: Treated Subjects
  This group will be treated with everolimus 7-28 days prior to surgery
  Intervention: Drug: Everolimus
• No Intervention: Reference Subjects
  This group will be enrolled as reference subjects, and will be undergoing routine surgery as part of standard of care treatment. No intervention will be provided to these subjects as part of the study.

• Publications *: Leitner DF, Kanshin E, Askenazi M, Siu Y, Friedman D, Devore S, Jones D, Ueberheide B, Wisniewski T, Devinsky O. Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia. PLoS One. 2022 May 19;17(5):e0268597. doi: 10.1371/journal.pone.0268597. eCollection 2022.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 1, 2020): 15
• Original Estimated Enrollment (submitted: May 21, 2015): 30
• Actual Study Completion Date: December 28, 2017
• Actual Primary Completion Date: December 8, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Patients: 1 year to 40 years. 2. Diagnosis: treatment resistant epilepsy due to Tuberous Sclerosis Complex or Focal Cortical Dysplasia Inclusion Criteria (Concurrent Comparison Group)

1. Patients: 1 year to 40 years. Matched for age (+/- 7 years) and sex of subjects in the treatment group.
2. Diagnosis: treatment resistant due to TSC or FCD. Matched for diagnosis of TSC and FCD.
3. Brain surgery for seizure control in which tissue is banked for research utilizing an existing IRB-approved study.

Exclusion Criteria

1. Treatment with an mTOR inhibitor (everolimus, sirolimus) during the past four weeks.
2. Known hypersensitivity to an mTOR inhibitor (everolimus, sirolimus)
3. Failure to establish diagnosis of treatment resistant epilepsy (i.e., adequate trials of two appropriately-chosen, tolerated and adequate trials of antiepileptic drugs) [32].
4. Exposure to any investigational agent in the month prior to study entry.
5. History of malignancy patients who are receiving anti-cancer treatments, such as radiation therapy and/or chemotherapy.
6. Patients with severe and/or uncontrolled medical conditions,
7. Patients on chronic corticosteroid therapy
8. A history of HIV seropositivity
9. Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the study;
10. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus;
11. Uncontrolled diabetes mellitus
12. Patients who have any severe and/or uncontrolled medical conditions
13. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus;

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 40 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02451696
• Other Study ID Numbers: 14-00245
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: NYU Langone Health
• Original Responsible Party: Same as current
• Current Study Sponsor: NYU Langone Health
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Orrin Devinsky, MD; NYU Langone Health

• PRS Account: NYU Langone Health
• Verification Date: August 2021